The principle goal of this project is to define the cellular states and signals that control the cell types and synapses in the central nervous system. The work in this program is based on the identification of stem cells in the nervous system. These cells can be obtained from the developing and adult nervous system and they can generate the differentiated cells of the nervous system, neurons, astrocytes and oligodendrocytes. In the past year, our studies of the fundamental biology of nervous system stem cells have: (1) defined the mechanisms that control the sub-cellular localization of a new nucleolar, p53 interacting protein (nucelostemin) that is specifically found in stem cells; (2) identified a molecular pathway controlling self-renewal in nervous system stem cells and (3) shown that notch activation controls proliferation and fate choice of nervous system stem cells. These studies, focused on the basic biology of nervous system stem cells, are now generating new insight into how interactions between signal pathways lead to the precise manipulation of cell number and type. The implications of this work in neuroscience are widely recognized but this recent work suggests that there will also be important gains in understanding the biology of cancer. The potential use in Parkinson?s disease of functional dopamine neurons derived from embryonic stem cells is a leading example of the clinical value of this new technology. Methods for directing ES cell differentiation to the dopamine fate are currently limited by our poor understanding of the normal development of the ventral midbrain where dopamine neurons are generated. In a program focused on the molecular biology of dopamine neuronal development we have shown that these neurons are derived from the floorplate, a glial structure previously thought to have an exclusively indirect effect on neurons. These data suggest that the genes and pathways regulating floor plate development will be important in the derivation of dopamine neurons and in the biology of Parkinson?s disease. The molecular biology of differentiated dopamine neurons is also a major focus in our group and we have made the interesting observation that a specific growth factor found in these mature neurons is associated with Parkinson?s disease. Our recent progress encourages us to believe that we are moving to a place where we will understand the signaling pathways controlling the disease, a pre-requisite for the development of rational new therapies.